1. Field of the Invention
This invention relates to novel imino-indeno[1,2-c]quinoline derivatives, which have been proven to have a broad and potent anticancer activity. This invention also relates to processes for preparing these derivatives, as well as the uses of the same in the manufacture of pharmaceutical compositions.
2. Description of the Related Art
A number of indenoisoquinolines, especially indeno[1,2-c]isoquinoline derivatives, have been synthesized and proven to possess DNA topoisomerase I (top I) inhibitory activity. Their mechanism of action is identical to that of the natural alkaloid camptothecin and its clinically useful derivative topotecan. These compounds bind to a transient top I-DNA covalent complex and inhibit the resealing of a single-strand nick that the top I creates to relieve superhelical tension in duplex DNA.
Since indenoisoquinolines were discovered as a novel class of potential anticancer drug candidates, extensive structural modifications have been explored by altering the substituent(s) of the tetracyclic pharmacophore thereof. However, synthesis and evaluation of the isomeric indenoquinoline skeleton attract only very limited attention.
The quinoline ring constitutes a wide variety of biologically active compounds and is frequently condensed with various heterocycles. For example, furo[2,3-b]quinoline derivatives have been synthesized and demonstrated to possess anticancer activity.
JP 09143166 A2 discloses condensed indan derivatives of formula (2a), which could be prepared by the following scheme:
in which the starting compounds of formula (3), the A ring and B ring of which independently represent a benzene ring optionally substituted with one or more groups selected from a halogen atom, a lower alkyl, a lower alkoxy, hydroxy, nitro, an alkoxycarbonyl and a lower alkylenedioxy, could be prepared from 2-oxo-3-phenyl4-quinoline carboxylic acid derivatives according to the process reported in Heterocyclic Chemistry, 16:487-491 (1979), and X is a halogen atom.
The substituent X of the condensed indan derivatives of formula (2a) could be further modified to a substituent R, which corresponds to the substituent R1 of formula (1) according to JP 09143166 A2 and which is defined to represent —NR3R4, an optionally substituted nitrogen-containing heterocyclic group or —OR5, in which R3 and R4 are independently selected from hydrogen, phenyl, an optionally substituted nitrogen-containing heterocyclic group or a lower alkyl group optionally substituted with an amino group, a lower alkoxy group, phenyl, a nitrogen-containing heterocyclic group and hydroxy, and in which R5 represents a lower alkyl group substituted with a substituted amino group.
However, the whole disclosure of JP 09143166 A2 only exemplifies the synthesis of the following compounds of formula (2a):
9-methoxy-6-[1-(4-methyl)piperazinyl]-11H-indeno[1,2-c]quinolin-11-one dihydrochloride (compound 1, in which R is 4-methyl-piperazinyl),
9-hydroxy-6-[1-(4-methyl)piperazinyl]-11H-indeno[1,2-c]quinolin-11-one dihydrochloride (compound 2, in which R is 4-methyl-piperazinyl),
9-methoxy-6N-[2-(dimethylamino)ethyl]amino-11H-indeno[1,2-c]quinolin-11-one dihydrochloride (compound 3, in which R is —NHCH2CH2N(CH3)2),
2,9-dimethoxy-6-[1-(4-methyl)piperazinyl]-11H-indeno[1,2-c]quinolin-11-one dihydrochloride (compound 4, in which R is 4-methyl-piperazinyl), and
2,9-dihydroxy-6-[1-(4-methyl)piperazinyl]-11H-indeno[1,2-c]quinolin-11-one dihydrochloride (compound 5, in which R is 4-methyl-piperazinyl).
In a previous study, the applicants synthesized certain indolo[2,3-b]quinoline derivatives and evaluated their anticancer activities on the ground that these tetracyclic heterocycles might intercalate into the DNA double helix, resulting in the inhibition of DNA replication and transcription.
In spite of the aforesaid, for pharmachemists and manufacturers in the Pharmaceutical Industry, there still exists a need to develop new compounds that can be easily prepared and that are suitable for use in the treatment of a variety of cancers and tumors.